Process and catalyst for the preparation of acetylpyridines

ABSTRACT

A process for the production of acetylopyridines of the formula (1): 
                         
by reacting a pyridinecarboxylic ester of the formula (II):
 
                         
wherein R 1  is C 1-6 -alkyl, with acetic acid in the gas phase in the presence of a catalyst. The active material of the catalyst is titanium dioxide and at least one alkali or alkaline earth metal oxide, and it is supported on an alumina-silica support having an apparent porosity of at least 50 percent. The process has the advantage of producing only small amounts of by-products (e.g, pyidine).

This is a 371 U.S. national stage application of International (PCT)Patent Application PCT/EP02/01533, filed on Feb. 14, 2002, that haspriority benefit of U.S. Provisional Application Ser. No. 60/332,546,filed on Nov. 26, 2001, and that has priority benefit of European PatentApplication No. 01103953.4, filed on Feb. 19, 2001.

The invention relates to a process for the production of acetylpyridinesof formula

in particular 3-acetylpyridine. It further relates to a catalystsuitable for the process of the invention.

3-Acetylpyridine is assuming increasing importance in the pharmaceuticaland fine chemical industry as an intermediate and a building block. Upto the present, 3-acetylpyridine has been prepared using oftenmultistage processes starting from nicotinic acid, or from otherstarting materials which are not readily available (for example3-ethylpyridine). Instead of using a heteroaromatic acid, it is possibleto use derivatives. This is particularly useful when the acid isnon-volatile and/or has a tendency to decompose at higher temperatures.Thus ethyl nicotinate was condensed with acetic acid at 520° C. to give37% yield of 3-acetylpyridine (Houben-Weyl, Vol. VI/2a, pp. 632–633).

Recently a process for the production of 3-acetylpyridine has beendescribed in EP-A-0 352 674, which utilises a catalyst based on titaniumdioxide and an alkali or alkaline earth metal oxide or hydroxide. Usingthe methyl ester of nicotinic acid and acetic acid and a catalystcomposed of 98% titanium dioxide (as anatase) and 2% sodium oxide,selectivities between 54% and 60% were reported. Pyridine was producedas a side product through decarboxylation of the nicotinate in amountsbetween 29 and 41%. Various other methods have been described which donot lead to satisfactory results (cf. EP-A-0 352 674).

The purpose of the present invention is to improve the selectivity ofthe state-of-the-art processes for 3-acetylpyridine, thus avoiding orreducing the losses caused by the formation of large quantities ofunwanted side-products.

According to the invention, this has been accomplished by the process ofthe invention.

It has been found that in the gas-phase reaction of pyridinecarboxylicesters of formula

wherein R¹ is C₁₋₆-alky, with acetic acid to give acetylpyridines (I)the selectivity of the titanium dioxide-based catalysts of EP-A-0 352674 can be substantially improved by employing a high-porosityalumina-silica support having an apparent porosity of at least 50%, asdetermined by the Archimedes method.

Preferably, the process according to the invention is carried out with aC₁₋₆-alkyl nicotinate as starting material to give 3-acetylpyridine.

It has further been found that by employing higher boilingpyridinecarboxylic esters (II) the ease of separation of the reactionproducts can be increased. Lower esters of e.g. nicotinic acid haveboiling points similar to those of the desired product, which results inseparation difficulties in distillation if the conversion is less than100%. Use of higher boiling (and more stable) esters largely avoids thisproblem. Examples of this are the butyl, pentyl or hexyl (including theisomers such as isobutyl, sec-butyl, isopentyl etc.) esters of nicotinicacid instead of methyl, ethyl or propyl esters, whose boiling points atatmospheric pressure differ only by 3–4 K (ethyl) and 15–16 K (methyland propyl), respectively, from that of 3-acetylpyridine. The differencein boiling point between butyl nicotinate and 3-acetylpyridine atatmospheric pressure is 32 K.

Preferably, pyridine carboxylic esters (II) having a boiling point (atatmospheric pressure) exceeding that of the product acetylpyridine (I)by more than 20 K are used as starting materials.

The preferred reaction temperature is 350 to 450° C.

Advantageously, the reaction is carried out in the presence of water andusing an excess of acetic acid.

The weight ratio of alumina to silica in the catalyst support isadvantageously between 70:30 and 90:10, preferably between 75:25 and85:15.

Preferably, the apparent porosity of the catalyst support is between 60and 70%.

The packing density of the catalyst support is preferably lower than1000 kg/m³, more preferably between 600 and 800 kg/m³.

Preferably, the titanium dioxide content of the catalyst is 5 to 20 wt.percent, based on the weight of the support.

The catalyst may be prepared by a process comprising the steps of (i)impregnating an alumina-silica support having an apparent porosity of atleast 50% with a solution of titanium tetrachloride in aqueoushydrochloric acid to obtain a first catalyst precursor, (ii) drying,(iii) calcining, (iv) impregnating the calcined first catalyst precursorwith a solution or suspension of a hydroxide and/or oxide of an alkalimetal and/or alkaline earth metal to obtain a second catalyst precursor,(v) drying and (vi) calcining the dried second catalyst precursor toobtain the final catalyst.

The impregnation of the support is not limited to the use of titaniumtetrachloride. Thus either other soluble salts of titanium, or even afinely-divided slurry of titanium oxide can be used. It is also possibleto replace the hydroxides or oxides of alkali or alkaline earth metalsby suitable precursors, e.g. salts of said metals which decompose onheating.

Advantageously, the ratio of alumina to silica in the support is between70:30 and 90:10, preferably between 75:25 and 85:15.

The apparent porosity of the catalyst support is preferably between 60and 70%.

Preferably, the titanium dioxide content of the catalyst is 5 to 20 wt.percent, based on the weight of the support.

The following non-limiting examples will illustrate the process of theinvention and the preparation of the catalyst of the invention.

EXAMPLE 1

Preparation of Catalyst:

For the preparation of the catalyst porous silica-alumina spheres areutilised as a support A suitable material is supplied by the NortonChemical Process Products Corporation of Akron, Ohio with the followingtypical specification:

Size and Shape: 4 mm Ø spheres Surface Area: 12 m²/g Apparent Porosity:65% Packing Density: 710 kg/m³ Total Pore Volume (by Hg porosimetry):0.5 ml/g Al₂O₃: 79–81% SiO₂: 17–19%

An aqueous solution of titanium tetrachloride (22% expressed as TiO₂,0.21 mol, 16 g) was prepared by adding 23 ml (40 g, 0.21 mol) of TiCl₄to a of 15 ml of concentrated hydrochloric acid and 60 ml ofdemineralised water. The final solution was stirred for several minutesand cooled down.

The above silica-alumina spheres (250 g) were impregnated in a rotatingglass vessel or metal drum using the wet incipient technique by sprayingthe TiCl₄ solution at 25–30° C. The catalyst precursor was subsequentlydried under vacuum (bath temperature: 90–95° C.) for 1 h, then at 120°C. for 12 h and finally calcined at 400° C. for 12 h under a stream ofair (500 ml/min). An analysis gave 7% Ti.

The calcined spheres were again placed in a rotating drum and sprayedwith dilute sodium hydroxide solution (1.5 g NaOH as a 5% aqueoussolution).

The catalyst was dried at 120° C. for 12 h and then calcined for 1 h at500° C.

EXAMPLE 2

Preparation of 3-acetylpyridine

An electrically heated tubular reactor with an inner diameter (i. d.) of12 mm was filled with 15 ml (12 g) of catalyst from example 1. Over aperiod of 12 h, a mixture of 17.9 g butyl nicotinate, 32 g water and 125g acetic acid was metered using a precision pump to the reactoroperating at 410° C. From the reaction mixture, 8.9 g of3-acetylpyridine, 0.9 g of pyridine and 1.3 g of butyl nicotinate wereobtained. This corresponded to a yield of 73% 3-acetylpyridine at abutyl nicotinate conversion of 93% (selectivity 78%). The selectivity ofpyridine formation was 11%.

COMPARATIVE EXAMPLE 1

Preparation of 3-acetylpyridine Using Catalyst Described in EP-A-0 352674

An electrically heated tubular reactor with an i. d. of 12 mm was filledwith 15 ml (≈15 g) of catalyst prepared according to EP-A-0 352 674,example 1. Over a period of 60 h, a mixture of methyl nicotinate (78 g),water (149 g) and acetic acid (523 g) was metered using a precision pumpto the reactor operating at 410° C. From the reaction mixture, 30.5 g of3-acetylpyridine, 8.5 g of pyridine and 9.0 g of methyl nicotinate wereobtained. This corresponded to a yield of 45% 3-acetylpyridine at amethyl nicotinate conversion of 88% (selectivity 50%). The selectivityof pyridine formation was 19%.

COMPARATIVE EXAMPLE 2

Preparation of 3-acetylpyridine Using Catalyst Described in EP-A-0 352674

An electrically heated tubular reactor with an i. d. of 12 mm was filledwith 15 ml (≈15 g) of catalyst prepared according to EP-A-0 352 674,example 1. Over a period of 63 h, a mixture of butyl nicotinate (104 g),water (162 g) and acetic acid (606 g) was metered using a precision pumpto the reactor operating at 405° C. From the reaction mixture, 30 g ofacetyl pyridine, 3 g of pyridine and 26 g of butyl nicotinate wereobtained. This corresponded to a yield of 43% 3-acetylpyridine at abutyl nicotinate conversion of 75% (selectivity 58%). The selectivity ofpyridine formation was 5%.

EXAMPLE 3

Preparation of 3-acetylpyridine

A tubular reactor with an i. d. of 23.5 mm was filled with 270 ml (≈227g) of catalyst from example 1. A mixture of butyl nicotinate (30 g/h),water (54 g/h) and acetic acid (210 g/h) was fed over an evaporatorusing a metering pump to the tubular reactor heated by a salt bath. Asmall flow of nitrogen (1 l/h) guaranteed the transport of the vapours.The temperature of the bath was 410° C. The reaction vapours werecondensed in an aqueous circulation system. After a total running timeof 35 h, the reaction solution was collected. A portion of this solutioncorresponding to a total of 710 g of butyl nicotinate was worked up toisolate the product. 81% of butyl nicotinate was converted to give 293 gof 3-acetyl-pyridine, corresponding to a selectivity of 75% and a yieldof 61%. The selectivity of pyridine formation was 4%.

1. A process for the preparation of an acetylpyridine of the formula:

comprising reacting a pyridinecarboxylic ester of the formula:

where R¹ is C₁₋₆-alkyl, with acetic acid in the gas phase in thepresence of a catalyst whose active material comprises titanium dioxideand at least one alkali or alkaline earth metal oxide, wherein thecatalyst comprises an alumina-silica support having an apparent porosityof at least 50 percent.
 2. The process of claim 1, wherein theacetylpyridine (I) prepared is 3-acetylpyridine and thepyridinecarboxylic ester (II) is a C₁₋₆-alkyl nicotinate.
 3. The processof claim 2, wherein the pyridinecarboxylix ester (II) has a boilingpoint at atmospheric pressure that is more than is more than 20° K. 4.The process of claim 3, wherein the reaction temperature is between 350and 450° C.
 5. The process of claim 4, wherein the weight ratio ofalumina to silica in the catalyst support is between 70:30 and 90:10. 6.The process of claim 5, wherein the apparent porosity of the catalystsupport is between 60 and 70 percent.
 7. The process of claim 6, whereinthe packing density of the catalyst support is between 600 and 1000kg/m³.
 8. The process of claim 7, wherein the titanium dioxide contentof the catalyst is 5 to 20 wt. percent, based on the weight of thesupport.
 9. The process of claim 4, wherein the weight ratio of aluminato silica in the catalyst support is between 75:25 and 85:15.
 10. Theprocess of claim 6, wherein the packing density of the catalyst supportis between 600 and 800 kg/m³.
 11. The process of claim 1, wherein thepyridinecarboxylic ester (II) has a boiling point at atmosphericpressure that is more than 20 higher than the boiling point of theacetylpyridine (I).
 12. The process of claim 1, wherein the reactiontemperature is between 350 and 450° C.
 13. The process of claim 1,wherein the weight ratio of alumina to silica in the catalyst support isbetween 70:30 and 90:10.
 14. The process of claim 1, wherein the weightratio of alumina to silica in the catalyst support is between 75:25 and85:15.
 15. The process of claim 1, wherein the apparent porosity of thecatalyst support is between 60 and 70 percent.
 16. The process of claim1, wherein the packing density of the catalyst support is between 600and 1000 kg/m³.
 17. The process of claim 1, wherein the packing densityof the catalyst support system is between 600 and 800 kg/m³.
 18. Theprocess of claim 1, wherein the titanium dioxide content of the catalystis 5 to 20 wt. percent, based on the weight of the support.